This application is the National Stage of International Application No. PCT/JP99/00470, filed Feb. 4, 1999.
The present invention relates to novel sulfonamide derivatives which are useful as a medicine and which inhibit activated coagulation factor X (FXa) to show anti-coagulant activity, their production and use.
For the purpose of the prevention and treatment of cardiac infarction, cerebral thrombosis, etc., it is important to inhibit formation of thrombus and various investigations and developments of thrombus inhibitors such as anti-thrombin agents, platelet aggregation inhibitors, etc. have been carried out. However, anti-thrombin agents as well as platelet aggregation inhibitors have side effects such as bleeding and safety problems. On the other hand, FXa inhibitors specifically inhibit the coagulation factor and are useful as anti-coagulants.
So far, compounds having FXa inhibitory activity are disclosed in e.g. Japanese Unexamined Patent Publication No. 1995 (H7)-112970, Japanese Unexamined Patent Publication No. 1993 (H5)-208946, WO 96/16940, WO 96/40679 and WO 96/10022, etc.
However, the above compounds having FXa inhibitory activity do not have sufficient FXa inhibitory activity and, in particular, do not show sufficient action when orally administered, therefore, they are not practically useful as a medicine.
The present invention is to provide novel sulfonamide derivatives which specifically inhibit FXa, which are effective when orally administered and which are useful as a safe medicine for the prevention (prophylaxis) or treatment (therapy) of diseases caused by thrombus or infarction.
The present inventors diligently made extensive studies and, as a result, they succeeded in synthesizing a compound or a salt thereof [hereinafter, referred to as Compound (I)], whose characteristic feature in the chemical structure lies in having (1) an oxo group on the ring A and (2) an optionally substituted amino group, an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group at the end of a substituent on the ring A, represented by the formula (I): 
wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; the ring A is an optionally substituted divalent nitrogen-containing heterocyclic group; Xxe2x80x2 is a chemical bond or an optionally substituted alkylene chain; Y is an optionally substituted divalent cyclic group; X is a chemical bond or an optionally substituted alkylene chain; and Z is (1) an optionally substituted amino group, (2) an optionally substituted imidoyl group or (3) an optionally substituted nitrogen-containing heterocyclic group; or a salt thereof, and further found that the compound (I) unexpectedly possesses potent FXa inhibitory activity based on its specific chemical structure and that the compound (I) can be safely and orally administered as a medicine for the prevention or treatment of diseases such as thrombus and infarction. Based on these findings the present invention was accomplished.
More specifically, the present invention relates to
(1) the Compound (I) or a salt thereof;
(2) a pro-drug of the Compound (I) or a salt thereof;
(3) a compound of the above (1) wherein R1 is an optionally substituted hydrocarbon group;
(4) a compound of the above (1) wherein R1 is an optionally substituted heterocyclic group;
(5) a compound of the above (1) wherein R1 is an aryl group optionally substituted with a halogen atom or C2-4 alkenyl group;
(6) a compound of the above (1) wherein R1 is a benzopyranyl group optionally substituted with a halogen atom;
(7) a compound of the above (1) wherein the ring A is 
xe2x80x83wherein n is 1 or 2, and m is 2 or 3;
(8) a compound of the above (1) wherein Xxe2x80x2 is an optionally substituted alkylene chain which may be substituted with 1-3 substituents selected from an optionally substituted lower alkyl group, an optionally substituted carbamoyl group, cyano group, hydroxy group and an optionally esterified carboxyl group;
(9) a compound of the above (1) wherein Y is an optionally substituted divalent cyclic hydrocarbon group, and Z is an optionally substituted amino group or an optionally substituted imidoyl group;
(10) a compound of the above (1) wherein Y is an optionally substituted divalent heterocyclic group;
(11) a compound of the above (1) wherein Y is an optionally substituted divalent heterocyclic group, and Z is an optionally substituted nitrogen-containing heterocyclic group;
(12) a compound of the above (1) wherein Y is an optionally substituted phenylene;
(13) a compound of the above (1) wherein Y is an optionally substituted piperidine;
(14) a compound of the above (1) wherein Z is an optionally substituted amidino group;
(15) a compound of the above (1) wherein Z is an optionally substituted nitrogen-containing heterocyclic group;
(16) A compound selected from the class consisting of 1-(4-amidinobenzyl)-4-(6-chloronaphthanlene-2-sulfonyl)-2-piperazinone, 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone, 4-(6-chloronaphthanlene-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 1-[1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, 4-(6-chloronaphthanlene-2-sulfonyl)-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone and 1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone or a salt thereof,
(17) a pro-drug of the compound as described in the above (16) or a salt thereof;
(18) a pharmaceutical composition comprising the compound (I) of the above (1) or a salt thereof;
(19) a composition of the above (18) which is an anti-coagulant;
(20) a composition of the above (18) which is an inhibitor of activated coagulation factor X;
(21) a composition of the above (18) which is for the prevention or treatment of cardiac infarction, cerebral thrombosis or deep vein thrombosis;
(22) use of the compound (I) of the above (1) or a salt thereof for manufacturing an anti-coagulant;
(23) use of the compound (I) of the above (1) or a salt thereof for manufacturing a pharmaceutical composition for inhibiting activated coagulation factor X;
(24) use of the compound (I) of the above (1) or a salt thereof for manufacturing a pharmaceutical composition for the prevention or treatment of cardiac infarction, cerebral thrombosis or deep vein thrombosis;
(25) a method for inhibiting coagulation in a mammal which comprises administering an effective amount of the compound (I) of the above (1) or a salt thereof;
(26) a method for inhibiting activated coagulation factor X in a mammal which comprises administering an effective amount of the compound (I) of the above (1) or a salt thereof;
(27) a method for preventing or treating cardiac infarction, cerebral thrombosis or deep vein thrombosis in a mammal which comprises administering an effective amount of the compound (I) of the above (1) or a salt thereof;
(28) A method for producing Compound (I) as described in the above (1) or a salt thereof by reacting Compound (II) or a salt thereof represented by the formula:
R1SO2Qxe2x80x83xe2x80x83(II)
xe2x80x83wherein Q is a halogen atom, and the other symbol is as defined in the above (1)
with Compound (III) or a salt thereof represented by the formula: 
wherein each symbol is as defined in the above (1); or producing Compound (I) as described in the above (1) or a salt thereof by reacting Compound (IV) or a salt thereof represented by the formula: 
wherein each symbol is as defined in the above (1) with Compound (V) or a salt thereof represented by the formula:
Q1xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x94Xxe2x80x94Zxe2x80x83xe2x80x83(V)
wherein Q1 is a halogen atom or a group of the formula:
R2xe2x80x94SO2xe2x80x94Oxe2x80x94
(wherein R2 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group), and the other symbols are as defined in the above (1); or producing Compound (Ia) as described in the above (1) or a salt thereof represented by the formula: 
wherein each symbol is as defined above by subjecting Compound (X) or a salt thereof represented by the formula: 
wherein X2 and X4 are respectively an optionally substituted alkylene chain, X3 is a chemical bond or an optionally substituted alkylene chain, R3 is a hydrogen atom or an optionally substituted hydrocarbon group, Q2is a halogen atom or a group of the formula:
R4xe2x80x94SO2xe2x80x94Oxe2x80x94
(wherein R4 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group), and the other symbols are as defined in the above (1) to ring closure reaction; or
producing Compound (Ib) as described in the above (1) or a salt thereof represented by the formula: 
wherein a combination of a broken line and a full line is a single bond or a double bond, and the other symbols are as defined above by subjecting Compound (XIII) or a salt thereof represented by the formula: 
wherein X5 is an optionally substituted alkylene chain, X6 is a chemical bond or an optionally substituted alkylene chain, R5 is a lower alkyl group, and the other symbols are as defined in the above (1) to ring closure reaction, and if desired, subjecting the obtained product to reduction; or
producing Compound (Ia) or a salt thereof represented by the formula: 
wherein each symbol is as defined above by subjecting Compound (VI) or a salt thereof represented by the formula: 
wherein X2 is an optionally substituted alkylene chain, and the other symbols are as defined in the above (1) and Compound (VII) or a salt thereof represented by the formula:
R3xe2x80x94(Cxe2x95x90O)xe2x80x94X3xe2x80x94Yxe2x80x94Xxe2x80x94Zxe2x80x83xe2x80x83(VII)
wherein X3 is a chemical bond or an optionally substituted alkylene chain, R3 is a hydrogen atom or an optionally substituted hydrocarbon group, and the other symbols are as defined in the above (1)
to reductive amination to produce Compound (VIII) or a salt thereof represented by the formula: 
wherein each symbol is as defined above, and reacting the obtained Compound (VIII) or a salt thereof with Compound (IX) represented by the formula:
Q2xe2x80x94X4xe2x80x94COOHxe2x80x83xe2x80x83(IX)
wherein X4 is an optionally substituted alkylene chain, Q2 is a halogen atom or a group of the formula:
R4xe2x80x94SO2xe2x80x94Oxe2x80x94
(wherein R4 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group), and the other symbols are as defined above or a salt thereof or its reactive derivative to produce Compound (X) or a salt thereof represented by the formula: 
wherein each symbol is as defined above, which is subjected to ring-closure reaction; or
producing Compound (Ib) or a salt thereof by reacting Compound (XI) or a salt thereof or its reactive derivative represented by the formula: 
wherein X5 is an optionally substituted alkylene chain, and the other symbols are as defined in the above (1) with Compound (XII) or a salt thereof represented by the formula:
Zxe2x80x94Xxe2x80x94Yxe2x80x94X6xe2x80x94NHCH2CH(OR5)2xe2x80x83xe2x80x83(XII)
wherein X6 is a chemical bond or an optionally substituted alkylene chain, R5 is a lower alkyl group, and the other symbols are as defined in the above (1) to produce Compound (XIII) or a salt thereof represented by the formula: 
wherein each symbol is as defined above, and subjecting the obtained Compound (XIII) or a salt thereof to ring-closure reaction with an acid to produce Compound (XIV) or a salt thereof represented by the formula: 
wherein each symbol is as defined above, and, if desired, reducing a double bond of the obtained Compound (XIV) or a salt thereof; or
producing Compound (I) as described in the above (1) or a salt thereof by reacting Compound (XX) or a salt thereof represented by the formula: 
wherein each symbol is as defined in the above (1) with Compound (XXI) or a salt thereof represented by the formula:
Zxe2x80x94X7xe2x80x94Q3
wherein X7 is a chemical bond or an optionally substituted alkylene chain, Q3 is a halogen atom or a group of the formula:
xe2x80x83R6xe2x80x94SO2xe2x80x94Oxe2x80x94
(wherein R6 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group), and the other symbol is as defined in the above (1); or producing Compound (XXV) or a salt thereof represented by the formula: 
wherein Zxe2x80x2 is an optionally substituted amidino group, and the other symbols are as defined above by reacting Compound (XXII) or a salt thereof represented by the formula: 
wherein each symbol is as defined in the above (1) with Compound (XXIII) or a salt thereof represented by the formula:
R7OH
wherein R7 is a lower alkyl group to produce Compound (XXIV) or a salt thereof represented by the formula: 
wherein each symbol is as defined above, and reacting the obtained Compound (XXIV) or a salt thereof with an amine, etc.
In the above formula, R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
Examples of the hydrocarbon group in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, etc. Among others, an aryl group, etc. is preferable.
Examples of the xe2x80x9caliphatic hydrocarbon groupxe2x80x9d exemplified by the hydrocarbon-group include e.g. a straight-chain or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, an alkynyl group, etc.
Examples of the alkyl group include e.g. a C1-10 alkyl group (preferably C1-6 alkyl, etc.), etc. such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methyl-heptyl, nonyl, etc.
Examples of the alkenyl group include e.g. C2-6 alkenyl group, etc. such as vinyl, allyl, isopropenyl, 2-methyl-allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.
Examples of the alkynyl group include e.g. a C2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,
Examples of the xe2x80x9calicyclic hydrocarbon groupxe2x80x9d exemplified by the hydrocarbon group include e.g. a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, a cycloalkanedienyl group, etc.
Examples of the xe2x80x9ccycloalkyl groupxe2x80x9d include e.g. C3-9 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.
Examples of the xe2x80x9ccycloalkenyl groupxe2x80x9d include e.g. C3-6 cycloalkenyl group, etc. such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc.
Examples of the xe2x80x9ccycloalkanedienyl groupxe2x80x9d include e.g. C4-6 cycloalkanedienyl group, etc. such as 2,4-cyclo-pentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclo-hexadien-1-yl, etc.
Examples of the xe2x80x9caryl groupxe2x80x9d exemplified by the hydrocarbon group include e.g. a monocyclic or fused aromatic hydrocarbon group. Among others, C6-14 aryl group, etc. such as phenyl, naphthyl, anthryl, phenathryl, acenaphthyl, etc. is preferable. In particular, phenyl, 1-naphthyl, 2-naphthyl, etc. are preferable.
Examples of the heterocyclic group in the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 include e.g. an aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (alicyclic heterocyclic group) etc., which contains, besides carbon atoms, at least one hetero-atom (preferably 1 to 4 hetero-atoms, more preferably 1 to 2 hetero-atoms)consisting of 1 to 3 kinds of hetero-atoms (preferably 1 to 2 kinds of hetero-atoms) selected from oxygen atom, sulfur atom, nitrogen atom, etc.
Examples of the xe2x80x9caromatic heterocyclic groupxe2x80x9d include an aromatic monocyclic heterocyclic group such as 5- to 6-membered aromatic monocyclic heterocyclic group, etc. (e.g. furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.); an aromatic fused heterocyclic group such as 8- to 12-membered aromatic fused heterocyclic group (preferably, heterocyclic group consisting of the above-mentioned 5 - or 6 -membered aromatic monocyclic heterocyclic group fused with a benzene ring or heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with the same or different above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group), etc. (e.g. benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.); etc.
Examples of the xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d include a 3-to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (alicyclic heterocyclic group), etc. such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc., or non-aromatic heterocyclic group wherein a part or all of the double bonds in the above-mentioned aromatic monocyclic heterocyclic group or aromatic fused heterocyclic group are saturated, etc. such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc.
Examples of the substituent of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 include an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl or cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted imidoyl group (e.g. a group of the formula:
xe2x80x94C(Uxe2x80x2)xe2x95x90Nxe2x80x94U
wherein U and Uxe2x80x2 are independently a hydrogen atom or a substituent (U is preferably a hydrogen atom), etc.), an optionally substituted amidino group (e.g. a group of the formula:
xe2x80x94C(NTxe2x80x2Txe2x80x3)xe2x95x90Nxe2x80x94T
wherein T, Txe2x80x2 and Txe2x80x3 are independently a hydrogen atom or a substituent (T is preferably a hydrogen atom), etc.), an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), a cyano group, a nitro group, an acyl group derived from a sulfonic acid, an acyl group derived from an carboxylic acid, etc.
The xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d may have 1 to 5 substituents as described above (preferably 1 to 3 substituents) at any possible position.
In addition, the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 may have an oxo group. For example, when R1 is a benzopyranyl, R1 may form benzo-xcex1-pyronyl, benzo-xcex3-pyronyl, etc.
Examples of the aryl group in the xe2x80x9coptionally substituted aryl groupxe2x80x9d as the substituent include C6-14 aryl group, etc. such as phenyl, naphthyl, anthryl, phenathryl, acenaphthyl, etc. Said aryl groups may have 1 to 3 substituents at any possible positions. Examples of the substituent include a lower alkoxy group (e.g. C1-6 alkoxy group, etc. such as methoxy, ethoxy, propoxy, etc.), a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, etc.), a lower alkenyl group (e.g. C2-6 alkenyl, etc. such as vinyl, allyl, etc.), a lower alkynyl group (e.g. C2-6 alkynyl group, etc. such as ethynyl, propargyl, etc.), an optionally substituted amino group, an optionally substituted hydroxy group, a cyano group, an optionally substituted amidino group, etc.
The xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxy groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d as the substituent are similar to those exemplified by the xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxy groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d, which the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 may have.
Examples of the cycloalkyl group in the xe2x80x9coptionally substituted cycloalkyl groupxe2x80x9d as the substituent include C3-7 cycloalkyl group, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Said cycloalkyl groups may have the same kind and number of substituents as those of the above described xe2x80x9coptionally substituted aryl groupxe2x80x9d.
Examples of the cycloalkenyl group in the xe2x80x9coptionally substituted cycloalkenyl groupxe2x80x9d as the substituent include e.g. C3-6 cycloalkenyl group, etc. such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. Said cycloalkenyl groups may have the same kind and number of substituents as those of the above described xe2x80x9coptionally substituted aryl groupxe2x80x9d.
Examples of the alkyl group in the xe2x80x9coptionally substituted alkyl groupxe2x80x9d as the substituent include e.g. C1-6 alkyl, etc. such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, etc. Said alkyl groups may have the same kind and number of substituents as those of the above described xe2x80x9coptionally substituted aryl groupxe2x80x9d.
Examples of the alkenyl group in the xe2x80x9coptionally substituted alkenyl groupxe2x80x9d as the substituent include e.g. C2-6 alkenyl group, etc. such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc. Said alkenyl groups may have the same kind and number of substituents as those of the above described xe2x80x9coptionally substituted aryl groupxe2x80x9d.
Examples of the alkynyl group in the xe2x80x9coptionally substituted alkynyl groupxe2x80x9d as the substituent include e.g. a C2-6 alkynyl group, etc. such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. Said alkynyl groups may have the same kind and number of substituents as those of the above described xe2x80x9coptionally substituted aryl groupxe2x80x9d.
Examples of the heterocyclic group in the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as the substituent include e.g. an aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (alicyclic heterocyclic group) etc., which contains, besides carbon atoms, at least one hetero-atom (preferably 1 to 4 hetero-atoms, more preferably 1 to 2 hetero-atoms)consisting of 1 to 3 kinds of hetero-atoms (preferably 1 to 2 kinds of hetero-atoms) selected from oxygen atom, sulfur atom, nitrogen atom, etc.
Examples of the xe2x80x9caromatic heterocyclic groupxe2x80x9d include an aromatic monocyclic heterocyclic group such as a 5- to 6-membered aromatic monocyclic heterocyclic group, etc. (e.g. furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.); an aromatic fused heterocyclic group such as 8- to 12-membered aromatic fused heterocyclic group (preferably, heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with a benzene ring or heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with the same or different above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group), etc. (e.g. benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.); etc.
Examples of the xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d include a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (alicyclic heterocyclic group), etc. such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc., or non-aromatic heterocyclic group wherein a part or all of the double bonds in the above-mentioned aromatic monocyclic heterocyclic group or aromatic fused heterocyclic group are saturated, etc. such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc.
Examples of the substituent of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as the substituent include a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, etc.), a lower alkenyl group (e.g. C2-6 alkenyl group, etc. such as vinyl, allyl, etc.), a lower alkynyl group (e.g. C2-6 alkynyl group, etc. such as ethynyl, propargyl, etc.), an acyl group (e.g. C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., benzoyl, etc.), an optionally substituted amino group, an optionally substituted hydroxy group, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), an optionally substituted imidoyl group, an optionally substituted amidino group, etc.
The xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxy groupxe2x80x9d, xe2x80x9can optionally substituted imidoyl groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d, which the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as the substituent may have, are similar to those exemplified by the xe2x80x9coptionally substitutedamino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxy groupxe2x80x9d, xe2x80x9can optionally substituted imidoyl groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d, which the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 may have.
Examples of the substituent in the xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted imidoyl groupxe2x80x9d, xe2x80x9coptionally substituted amidino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxy groupxe2x80x9d and xe2x80x9coptionally substituted thiol groupxe2x80x9d as the substituent, which xe2x80x9cthe optionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9cthe heterocyclic groupxe2x80x9d represented by R1 may have, include e.g. a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, an acyl group such as C1-6 alkanoyl (e.g. formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl, etc., an optionally halogenated C1-6 alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, trifluoromethoxy-carbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloro-methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), a heterocyclic group (e.g. the above described xe2x80x9cheterocyclic groupxe2x80x9d similar to xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1; preferably, pyridyl; more preferably, 4-pyridyl; etc.), etc. In addition, the xe2x80x9camino groupxe2x80x9d in the xe2x80x9coptionally substituted amino groupxe2x80x9d as the substituent may be substituted with an optionally substituted imidoyl group (e.g., C1-6 alkylimidoyl, C1-6 alkanoylimidoyl (e.g. formimidoyl, etc.), amidino, etc.), an amino group optionally substituted with 1-2 C1-6 alkyl groups, etc. and two substituents of the xe2x80x9camino groupxe2x80x9d may form a cyclic amino group together with a nitrogen atom. Examples of said cyclic amino group include e.g. 3- to 8-membered (preferably 5- to 6-membered)cyclic amino group, etc. such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and 1-piperazinyl which may have at the 4-position a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g. C7-10 aralkyl group, etc. such as benzyl, phenethyl, etc.), an aryl group (e.g. C6-10 aryl group, etc. such as phenyl, 1-naphthyl, 2-naphthyl, etc.), etc.
Examples of the xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d include unsubstituted carbamoyl, N-mono-substituted carbamoyl group and N,N-di-substituted carbamoyl group.
The xe2x80x9cN-mono-substituted carbamoyl groupxe2x80x9d is a carbamoyl group having one substituent on the nitrogen atom and said substituent include e.g. a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), a lower alkenyl group (e.g. C2-6 alkenyl group, etc. such as vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, hexenyl, etc.), a cycloalkyl group (e.g. C3-6 cycloalkyl group, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an aryl group (e.g. C6-10 aryl group, etc. such as phenyl, 1-naphthyl, 2-naphthyl, etc.), an aralkyl group (e.g. C7-10 aralkyl group, preferably phenyl-C1-4 alkyl group, etc. such as benzyl, phenethyl, etc.), arylalkenyl group (e.g., C8-10 arylalkenyl group such as cinnamyl, etc., preferably phenyl-C2-4 alkenyl group, etc.), a heterocyclic group (e.g. the above described xe2x80x9cheterocyclic groupxe2x80x9d as the substituent of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1, etc.), etc.
Said lower alkyl group, lower alkenyl group, cycloalkyl group, aryl group, aralkyl group, aralkenyl group and heterocyclic group may have a substituent and examples of the substituent include e.g. a hydroxy group, an optionally substituted amino group [said amino group may have 1 to 2 substituents (e.g. a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (e.g. C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., benzoyl, etc.), a carboxyl group, C1-6 alkoxy-carbonyl group, etc.)], a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a lower alkyl group optionally substituted with 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkoxy group optionally substituted with 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.), etc.
Said lower alkyl group include e.g. C1-6 alkyl group, etc. such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. and in particular methyl, ethyl, etc. are preferable. Said lower alkoxy group include e.g. C1-6 alkoxy group, etc. such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. and in particular methoxy, ethoxy, etc. are preferable.
These substituents may be same or different and the number of the substituents is preferably 1 or 2 to 3 (more preferably 1 or 2).
The xe2x80x9cN,N-di-substituted carbamoyl groupxe2x80x9d is a carbamoyl group having two substituents on the nitrogen atom. Examples of one of the substituents include the same as those of the above described xe2x80x9cN-mono-substituted carbamoyl groupxe2x80x9d and examples of the other substituent include e.g. a lower alkyl group (e.g. C1-6 alkyl group, etc. suchasmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), C3-6 cycloalkyl group (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C7-10 aralkyl group (e.g. benzyl, phenethyl, etc., preferably phenyl-C1-4 alkyl group, etc.), etc. In addition, two substituents of the xe2x80x9cN,N-di-substituted carbamoyl groupxe2x80x9d may form a cyclic amino-carbamoyl group together with a nitrogen atom. Examples of said cyclic amino-carbamoyl group include e.g. 3- to 8-membered (preferably 5- to 6-membered)cyclic amino-carbamoyl group, etc. such as 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholino-carbonyl, 1-piperazinylcarbonyl and 1-piperazinylcarbonyl which may have at the 4-position a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g. C7-10 aralkyl group, etc. such as benzyl, phenethyl, etc.), an aryl group (e.g. C6-10 aryl group, etc. such as phenyl, 1-naphthyl, 2-naphthyl, etc.), etc.
Examples of the substituent in the xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d include the same substituent as those in the above described xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d.
Examples of the xe2x80x9coptionally esterified carboxyl groupxe2x80x9d in the present specification include a carboxyl group as well as a lower alkoxycarbonyl group, an aryloxycarbonyl group, aralkyloxycarbonyl group, etc.
Examples of the xe2x80x9clower alkoxycarbonyl groupxe2x80x9d include e.g. C1-6 alkoxy-carbonyl group, etc. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxy-carbonyl, neopentyloxycarbonyl, etc. Among others, C1-3 alkoxy-carbonyl group, etc. such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc. are preferable.
Examples of the xe2x80x9caryloxycarbonyl groupxe2x80x9d include e.g. C7-12 aryloxy-carbonyl group, etc. such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, etc.
Examples of the xe2x80x9caralkyloxycarbonyl groupxe2x80x9d include e.g. C7-10 aralkyloxy-carbonyl group, etc. (preferably, C6-10 aryl-C1-4 alkoxy-carbonyl, etc.) such as benzyloxycarbonyl, phenethyloxycarbonyl, etc.
Said xe2x80x9caryloxycarbonyl groupxe2x80x9d and xe2x80x9caralkyloxycarbonyl groupxe2x80x9d may have a substituent. Examples of the substituent include the same kind and number of the substituents of the aryl group and aralkyl group as the substituent for the above described N-mono-substituted carbamoyl group.
Examples of the xe2x80x9cacyl group derived from a sulfonic acidxe2x80x9d as the substituent include a sulfonyl group having one substituent which the above described xe2x80x9cN-mono-substituted carbamoyl groupxe2x80x9d have on the nitrogen atom, etc., preferably, C1-6 alkylsulfonyl, etc. such as methanesulfonyl, ethane-sulfonyl, etc.
Examples of the xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d as the substituent include a carbonyl group having a hydrogen atom or one substituent which the above described xe2x80x9cN-mono-substituted carbamoyl groupxe2x80x9d have on the nitrogen atom, etc., preferably, C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc. benzoyl, etc.
As R1, an optionally substituted hydrocarbon group is preferable. Among others, an aryl group (preferably, C6-14 aryl group, etc. such as phenyl, 1-naphthyl, 2-naphthyl, etc.) optionally substituted with a halogen atom or C2-4 alkenyl group.
Also, as R1, an optionally substituted heterocyclic group is preferable. Among others, a heterocyclic group (preferably, benzofuranyl group, benzopyranyl group, etc., more preferably benzopyranyl group) optionally substituted with a halogen atom.
In the above formula, the ring A is an optionally substituted divalent nitrogen-containing heterocyclic group. That is, the ring A is a divalent nitrogen-containing heterocyclic group which may have an optional substituent at any possible position, in addition to one oxo group clearly described as a substituent on the ring A. Said oxo group may be present at any possible position, preferably on the carbon atom next to the nitrogen atom to which the group of the formula:
xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x94Xxe2x80x94Z
binds.
Examples of the xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in the xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d represented by the ring A include a divalent 6- to 8-membered nitrogen-containing heterocyclic group having an oxo group at any possible position and which contains, besides carbon atoms, at least two nitrogen atoms and which may contain 1 to 3 hetero-atoms selected from oxygen atom, sulfur atom, etc. and preferably a divalent 6- to 8-membered nitrogen-containing heterocyclic group having an oxo group at any possible position and which contains, besides carbon atoms, at least two nitrogen atoms.
Examples of the xe2x80x9cdivalent 6- to 8-membered nitrogen-containing heterocyclic groupxe2x80x9d include e.g. a divalent 6-membered nitrogen-containing heterocyclic group which contains 2 to 4 nitrogen atoms such as piperazinediyl (piperazine-1,4-diyl, etc.), tetrahydropyrazinediyl, triazacyclohexanediyl, tetraazacyclohexanediyl, tetrahydrotriazinediyl, etc.; a divalent 7-membered nitrogen-containing heterocyclic group which contains 2 to 4 nitrogen atoms such as homopiperazinediyl (piperazine-1,4-diyl, etc.), 2,3-dehydrohomopiperazinediyl, etc.; a divalent 8-membered nitrogen-containing heterocyclic group which contains 2 to 4 nitrogen atoms such as 1,4-diazacyclooctanediyl (1,4-diazacyclooctane-1,4-diyl, etc.), 1,5-diazacyclo-octanediyl (1,5-diazacyclooctane-1,5-diyl, etc.) etc.; etc.
These xe2x80x9cdivalent nitrogen-containing heterocyclic groupsxe2x80x9d have an oxo group at any possible position. Among others, xe2x80x9cdivalent 6-8 membered nitrogen-containing cyclic amide groupxe2x80x9d having an oxo group on the carbon atom next to the nitrogen atom to which the group of the formula:
xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x94Xxe2x80x94Z
binds is preferable.
Examples of the xe2x80x9cdivalent 6-8 membered nitrogen-containing cyclic amide groupxe2x80x9d include 2-oxopiperazine-1,4-diyl, 2-oxo-1,2,3,4-tetrahydropyrazine-1,4-diyl, 2-oxohomopiperazine-1,4-diyl, 5-oxohomopiperazine-1,4-diyl, 2-oxo-1,4-diazacyclooctane-1,4-diyl, 5-oxo-1,4-diazacyclooctane-1,4-diyl, 2-oxo-1,5-diazacyclooctane-1,5-diyl, 5-oxo-2,3-dehydrohomopiperazine-1,4-diyl, 3-oxo-1,2,4-triazacyclohexane-1,4-diyl, 3-oxo-1,2,3,4-tetrahydro-1,2,4-triazine-1,4-diyl, 6-oxo-1,2,4-triazacyclohexane-1,4-diyl, 3-oxo-1,2,4,5-tetraazacyclohexane-1,4-diyl, etc.
Examples of the substituents of the xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in the xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d represented by the ring A include, in addition to one oxo group, e.g. an optionally substituted hydroxy group, an optionally substituted thiol group, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkylidene group, an optionally substituted lower aralkylidene group, a lower alkoxy group optionally substituted with 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.), an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfurmoyl group, etc. Said xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d may have 1 to 3 (preferably 1 to 2) of these substituents at any possible position.
Examples of the substituents of the xe2x80x9coptionally substituted amino groupxe2x80x9d include 1-2 substituents selected from an optionally substituted alkyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfurmoyl group, an optionally esterified carboxyl, an acyl group derived from a sulfonic acid, an acyl group derived from a carboxylic acid, etc. Examples of said xe2x80x9coptionally substituted alkyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9can optionally substituted thiocarbamoyl groupxe2x80x9d, xe2x80x9can optionally substituted sulfurmoyl groupxe2x80x9d, xe2x80x9can optionally esterified carboxyl groupxe2x80x9d, xe2x80x9can acyl group derived from a sulfonic acidxe2x80x9d and xe2x80x9can acyl group derived from a carboxylic acidxe2x80x9d include the xe2x80x9coptionally substituted alkyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9can optionally substituted thiocarbamoyl groupxe2x80x9d, xe2x80x9can optionally substituted sulfurmoyl groupxe2x80x9d, xe2x80x9can optionally esterified carboxyl groupxe2x80x9d, xe2x80x9can acyl group derived from a sulfonic acidxe2x80x9d and xe2x80x9can acyl group derived from a carboxylic acidxe2x80x9d as exemplified by the substituents for the above described xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
Preferable examples of the xe2x80x9coptionally substituted amino groupxe2x80x9d include an amino group optionally substituted by 1-2 substituents selected from (1) a lower (C1-6) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., (2) mono- or di-lower (C1-6) alkylcarbamoyl group, (3) C1-6 alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, etc., (4) C3-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc. and (5) benzoyl.
Examples of the xe2x80x9clower alkyl groupxe2x80x9d in the xe2x80x9cthe optionally substituted a lower alkyl groupxe2x80x9d include e.g. C1-6 alkyl group, etc. such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and in particular methyl, ethyl, etc. are preferable.
Examples of the substituents for the xe2x80x9clower alkyl groupxe2x80x9d include e.g. a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), an amino group, a carboxyl group, hydroxy group, C6-10 aryl, C6-10 aryloxy, etc. Said xe2x80x9clower alkyl groupxe2x80x9d may have 1 to 5 (preferably 1 or 2) substituents at any possible position.
Examples of the xe2x80x9coptionally substituted lower alkylidene groupxe2x80x9d include e.g. C1-6 alkylidene, etc. such as methylidene, ethylidene, etc. Examples of the substituents for the xe2x80x9clower alkylidene groupxe2x80x9d include e.g. a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), an amino group, a carboxyl group, a hydroxy group, etc. Said xe2x80x9clower alkylidene groupxe2x80x9d may have 1 to 5 (preferably 1 to 2) of these substituents at any possible position.
Examples of the xe2x80x9coptionally substituted lower aralkylidene groupxe2x80x9d include e.g. C6-10 aryl-C1-4 alkylidene, etc. such as benzylidene, etc. Examples of the substituents for the xe2x80x9clower aralkylidene groupxe2x80x9d include e.g. a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), an amino group, a carboxyl group, a hydroxy group, etc. Said xe2x80x9clower aralkylidene groupxe2x80x9d may have 1 to 5 (preferably 1 to 2) of these substituents at any possible position.
Examples of the xe2x80x9clower alkoxy groupxe2x80x9d in the xe2x80x9clower alkoxy group optionally substituted with 1 to 5 halogen atomsxe2x80x9d include e.g. C1-6 alkoxy group, etc. such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. and in particular methoxy, ethoxy, etc. are preferable.
Examples of the xe2x80x9coptionally esterified carboxyl groupxe2x80x9d include the optionally esterified carboxyl group as exemplified by the substituents for the above described xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
Examples of the xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9can optionally substituted thiocarbamoyl groupxe2x80x9d and xe2x80x9can optionally substituted sulfurmoyl groupxe2x80x9d include the optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group and an optionally substituted sulfurmoyl group as exemplified by the substituents for the above described xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
Examples of the substituents for the xe2x80x9chydroxy groupxe2x80x9d and xe2x80x9cmercapto groupxe2x80x9d in the xe2x80x9coptionally substituted hydroxy groupxe2x80x9d and xe2x80x9coptionally substituted mercapto groupxe2x80x9d as a substituent, which the xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d represented by the ring A may have, include an optionally substituted lower alkyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfurmoyl group, an acyl group derived from a sulfonic acid, an acyl group derived from a carboxylic acid, etc.
Examples of the lower alkyl group include e.g. C1-6 alkyl group, etc. such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. Examples of the substituents, which said lower alkyl group may have, include a halogen atom(e.g., fluorine, chlorine, bromine, iodine, etc.), an optionally substituted aryl group [e.g. phenyl or naphthyl, each of which may be substituted with a halogen atom(e.g., fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (e.g., C1-6 alkyl group, etc. such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), a lower alkoxy group (e.g., C1-6 alkoxy group, etc. such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), etc.], an optionally substituted hydroxy group (e.g., similar to the optionally substituted hydroxy group as a substituent for the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by the above-mentioned R1, etc.), an optionally substituted thiol group (e.g., similar to the optionally substituted thiol group as a substituent for the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by the above-mentioned R1, etc.), an optionally substituted amino group (e.g., similar to the optionally substituted amino group as a substituent for the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by the above-mentioned R1, etc.), an optionally esterified carboxyl group (e.g., similar to the optionally esterified carboxyl group as a substituent for thexe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by the above-mentioned R1, etc.), etc. In addition, a sulfur atom in the xe2x80x9coptionally substituted mercapto groupxe2x80x9d may be oxidized. For example, the sulfur atom may be in the form of the formula:
S(O)k[k is an integer of 0 to 2].
Examples of the xe2x80x9coptionally esterified carboxyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted sulfurmoyl groupxe2x80x9d, xe2x80x9cacyl group derived from a sulfonic acidxe2x80x9d and xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d as a substituent for the xe2x80x9chydroxy groupxe2x80x9d and xe2x80x9cmercapto groupxe2x80x9d in the xe2x80x9coptionally substituted hydroxy groupxe2x80x9d and xe2x80x9coptionally substituted mercapto groupxe2x80x9d, which the xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d represented by the ring A may have, are similar to the xe2x80x9coptionally esterified carboxyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted sulfurmoyl groupxe2x80x9d, xe2x80x9cacyl group derived from a sulf onic acidxe2x80x9d and xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d as a substituent for the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by the above-mentioned R1.
As the ring A, a group of the formula: 
wherein n is 1 or 2, and m is 2 or 3, etc. is preferable.
In the above formula, m is preferably 2, and n is preferably 1.
In particular, the ring A is preferably 2-oxopiperazine-1,4-diyl.
In the above formula, Y is an optionally substituted divalent cyclic group.
Examples of the substituents for the xe2x80x9coptionally substituted divalent cyclic groupxe2x80x9d represented by Y include the same substituents as those of the above described xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d represented by the ring A.
As a substituent for the xe2x80x9cdivalent cyclic groupxe2x80x9d represented by Y, an optionally substituted hydroxy group is preferable and, among others, hydroxy group and C1-6 alkanoyloxy (e.g., acetoxy, etc.) are preferable.
When Y is a divalent saturated nitrogen-containing heterocyclic group (in particular, piperidine-1,4-diyl), the substituent for Y is preferably present on the carbon atom to which the group Xxe2x80x2 binds.
Examples of the xe2x80x9cdivalent cyclic groupxe2x80x9d in the xe2x80x9coptionally substituted divalent cyclic groupxe2x80x9d include a divalent cyclic hydrocarbon group or a divalent heterocyclic group (preferably, a divalent heterocyclic group).
Examples of the xe2x80x9cdivalent cyclic hydrocarbon groupxe2x80x9d in the xe2x80x9cdivalent cyclic groupxe2x80x9d of the xe2x80x9coptionally substituted divalent hydrocarbon groupxe2x80x9d represented by Y include a saturated or unsaturated cyclic divalent hydrocarbon group, etc. . . .
Examples of the saturated cyclic divalent hydrocarbon group include a divalent group formed by removing a hydrogen atom at an optional position (preferably a hydrogen atom on a carbon atom which is different from the carbon atom at the 1-position, more preferably a hydrogen atom on a carbon atom which is farthest from the carbon atom at the 1-position) from a cycloalkyl group (e.g. C3-9 cycloalkyl (preferably C5-7 cycloalkyl, more preferably cyclohexyl, etc.), etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, cyclooctyl, cyclononyl, etc.). Preferable examples of the saturated cyclic divalent hydrocarbon group include C5-7 cycloalkylene (more preferably 1,4-cyclohexylene, etc.), etc.
Examples of the unsaturated cyclic divalent hydrocarbon group include a divalent group formed by removing a hydrogen atom at an optional position (preferably a hydrogen atom on a carbon atom which is different from the carbon atom at the 1-position, more preferably a hydrogen atom on a carbon atom which is farthest from the carbon atom at the 1-position) from a cycloalkenyl group (e.g. C3-6 cycloalkenyl group, etc. such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc.), a cycloalkanedienyl group (e.g. C4-6 cycloalkanedienyl group, etc. such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, etc.), an aryl group (e.g. C6-10 aryl group, etc. such as phenyl, naphthyl, etc., preferably phenyl), etc. Among others, phenylene is preferable and in particular 1,4-phenylene is preferable.
As the xe2x80x9cdivalent hydrocarbon groupxe2x80x9d, C5-7 cycloalkylene (preferably 1,4-cyclohexylene, etc.), phenylene (preferably 1,4-phenylene, etc.), etc. are preferable.
Examples of the xe2x80x9cdivalent heterocyclic groupxe2x80x9d in the xe2x80x9coptionally substituted divalent heterocyclic groupxe2x80x9d represented by Y include a 5- to 6-membered divalent aromatic heterocyclic group, a 5- to 6-membered divalent saturated or unsaturated non-aromatic heterocyclic group (alicyclic heterocyclic group), etc., which contains, besides carbon atoms, at least one hetero-atom (preferably 1 to 3 hetero-atoms, more preferably 1 to 2 hetero-atoms)consisting of 1 to 3 kinds of hetero-atoms (preferably 1 to 2 kinds of hetero-atoms) selected from oxygen atom, sulfur atom, nitrogen atom, etc.
Examples of the xe2x80x9cdivalent aromatic heterocyclic groupxe2x80x9d include a divalent group formed by removing two hydrogen atoms at different positions from a 5-membered heterocyclic ring such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, etc., a 6-membered heterocyclic ring such as pyridine, pyridazine, pyrimidine, 1,2,4-triazine, 1,3,5-triazine, etc.
Examples of the xe2x80x9cdivalent non-aromatic heterocyclic groupxe2x80x9d include a 5- to 6-membered saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (alicyclic heterocyclic group), etc. such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, etc.
Among others, Y is preferably an optionally substituted phenylene, an optionally substituted piperidine, etc.
In addition, when the xe2x80x9cdivalent cyclic groupxe2x80x9d in the xe2x80x9coptionally substituted divalent cyclic groupxe2x80x9d represented by Y is a divalent cyclic hydrocarbon group, Z is preferably an optionally substituted amino group or an optionally substituted imidoyl group. When the xe2x80x9cdivalent cyclic groupxe2x80x9d in the xe2x80x9coptionally substituted divalent cyclic groupxe2x80x9d represented by Y is a divalent heterocyclic group, Z is preferably an optionally substituted nitrogen-containing heterocyclic group.
In the above formula, X and Xxe2x80x2 are independently a chemical bond or an optionally substituted alkylene chain.
Examples of the xe2x80x9calkylene chainxe2x80x9d in the xe2x80x9coptionally substituted alkylene chainxe2x80x9d represented by X and Xxe2x80x2 include a straight-chain lower (C1-6) alkylene, etc. such as methylene, ethylene, propylene, butylene, pentylene, etc. Among others, C1-4 alkylene, etc. such as methylene, ethylene, etc. is preferable.
Examples of the substituents for thexe2x80x9calkylene chainxe2x80x9d include a lower alkyl group [similar to thexe2x80x9coptionally substituted lower alkyl groupxe2x80x9d as a substituent for the xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d for the above-mentioned the ring A, etc.; preferably, loweralkyl group (e.g. C1-6 alkyl, etc. such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.)], an optionally substituted carbamoyl group [similar to thexe2x80x9coptionally substituted carbamoyl groupxe2x80x9d as a substituent for the xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d for the above-mentioned the ring A, etc.; preferably, carbamoyl group, N-mono-lower (C1-6) alkylcarbamoyl group, N,N-di-lower (C1-6)alkylcarbamoyl group, etc.], cyano group, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), hydroxy group, an optionally esterified carboxyl group (the same xe2x80x9coptionally esterified carboxyl groupxe2x80x9d as exemplified by the substituents for the above described xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1), etc. Saidxe2x80x9calkylene chainxe2x80x9d may have 1 to 3 of these substituents at any possible position.
In the above formula, Z is (1) an optionally substituted amino group, (2) an optionally substituted imidoyl group or (3) an optionally substituted nitrogen-containing heterocyclic group.
Examples of the substituents for the xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Z are similar to those for the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by the above-mentioned R1. Two of the substituents for the xe2x80x9coptionally substituted amino groupxe2x80x9d may bind to each other to form a cyclic amino group together with a nitrogen atom. Examples of said cyclic amino group include 3-8 membered (preferably 5-6 membered) cyclic amino, etc. such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and 1-piperazinyl which may have at the 4-position a lower alkyl group (e.g. C1-6 alkyl group, etc. such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), aralkyl group (e.g. C7-10 aralkyl group, etc. such as benzyl, phenethyl, etc.), aryl group (e.g. C6-10 aryl group, etc. such as phenyl, 1-naphthyl, 2-naphthyl, etc.), etc., etc. Said cyclic amino group may have similar number and kinds of the substituents to those for the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by the above-mentioned R1.
When the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d as a substituent in the xe2x80x9camino group substituted with optionally substituted hydrocarbon groupxe2x80x9d represented by Z include xe2x80x9can optionally substituted imino groupxe2x80x9d in its xcex1-position, the xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Z forms an amino group substituted with xe2x80x9can optionally substituted imidoyl groupxe2x80x9d exemplified below as Z. For example, a group of the formula:
xe2x80x94N(Rxe2x80x3)xe2x80x94C(Rxe2x80x2)xe2x95x90Nxe2x80x94R
[wherein Rxe2x80x3 is a hydrogen atom or an optionally substituted hydrocarbon group, R is a hydrogen atom, an optionally substituted hydroxy group, an optionally substituted hydrocarbon group or an acyl group derived from a carboxylic acid, and Rxe2x80x2 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group derived from a carboxylic acid, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted hydroxy group], etc. is also included by the xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Z.
In addition, when Rxe2x80x2 is a mercapto group or a hydroxy group and R is a hydrogen atom in the xe2x80x9coptionally substituted imidoyl groupxe2x80x9d, said xe2x80x9coptionally substituted imidoyl groupxe2x80x9d may be in the form of a group of the formula:
xe2x80x94C(xe2x95x90O)xe2x80x94NH2
or
xe2x80x94C(xe2x95x90S)xe2x80x94NH2.
In the above formula, the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R, Rxe2x80x2 and Rxe2x80x3 are the same as the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1. Examples of the xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d represented by R and Rxe2x80x2 include that exemplified by the xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d as the substituent for the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1. Examples of the xe2x80x9coptionally substituted hydroxy groupxe2x80x9d represented by Rxe2x80x2 include that exemplified by the xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as the substituent for the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1. Examples of the xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Rxe2x80x2 include that exemplified by the xe2x80x9coptionally substituted amino groupxe2x80x9d as the substituent for the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1; or an amino group which may have 1-2 xe2x80x9coptionally substituted hydrocarbon groupsxe2x80x9d represented by the above-mentioned R1; etc.
In the compound represented by the formula (I), compounds wherein R is an acyl group derived from a carboxylic acid is useful as a pro-drug for compounds wherein R is a hydrogen atom.
Examples of the xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d represented by R include that exemplified by the xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d as the substituent for the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1. In addition, the xe2x80x9cacyl group derived from a carboxylic acidxe2x80x9d represented by R may be, for example, a group of the formula:
xe2x80x94COORxe2x80x2xe2x80x3
wherein Rxe2x80x2xe2x80x3 is an optionally substituted hydrocarbon group, etc., such as an optionally esterified carboxyl group, etc. Examples of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by Rxe2x80x2xe2x80x3 include that exemplified by the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
Preferred examples of the xe2x80x9chydrocarbon groupxe2x80x9d in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by Rxe2x80x2xe2x80x3 include C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, etc. Said xe2x80x9chydrocarbon groupxe2x80x9d may have similar number and kinds of the substituents to those for the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
Among others, specific examples of the group represented by the formula:
xe2x80x94COORxe2x80x2xe2x80x3
include C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, etc.), C1-6 alkanoyloxy-C1-6 alkoxy-carbonyl group (e.g., pivaloyloxymethoxycarbonyl, 1-(acetoxy)ethoxycarbonyl, acetoxy-tert-butoxycarbonyl, etc.), C1-6 alkoxy-carbonyloxy-C1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyloxymethoxycarbonyl, etc.), 5-C1-4 alkyl-2-oxo-dioxol-4-yl-C1-6 alkoxy-carbonyl group (e.g., 5-methyl-2-oxo-dioxol-4-ylmethoxycarbonyl, etc.), etc.
More specific examples of the xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Z include a mono- or di-lower (C1-6) alkylamino group (e.g. methylamino, ethylamino, benzylmethylamino, dimethylamino, diethylamino, diisobutylamino, diisopropylamino, N-ethyl-t-butylamino, benzylmethylamino, etc.) which may be further substituted with an amino group, a C6-10 aryl group (preferably, phenyl), etc.; a group of the formula:
xe2x80x94N(Rxe2x80x3)xe2x80x94C(Rxe2x80x2)xe2x95x90Nxe2x80x94R
[wherein Rxe2x80x3 is a hydrogen atom or an optionally substituted hydrocarbon group (preferably, a hydrogen atom or a lower (C1-6) alkyl group), R is a hydrogen atom, an optionally substituted hydrbxy group, an optionally substituted hydrocarbon group or an acyl group derived from a carboxylic acid (preferably, a hydrogen atom or an acyl group derived from a carboxylic acid), and R1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted hydroxy group (preferably, a hydrogen atom, a lower (C1-6) alkyl group, an amino group or a mono- or di-lower (C1-6) alkylamino group)] (e.g., guanidino group, formimidoylamino group, acetimidoylamino group, etc.); 5-6 membered cyclic amino group (e.g., piperidino group, etc.); etc.
Examples of the xe2x80x9coptionally substituted imidoyl groupxe2x80x9d represented by Z include a group of the formula:
xe2x80x94C(Rxe2x80x2)xe2x95x90Nxe2x80x94R
wherein each symbol is as defined above, etc.
Here, when Rxe2x80x2 is an optionally substituted amino group (preferably, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, hydrazino, piperidino, piperazino, morpholino, thiomorpholino, etc.), the xe2x80x9coptionally substituted imidoyl groupxe2x80x9d represented by Z forms an optionally substituted amidino group. Examples of said optionally substituted amidino group include an amidino group optionally substituted with 1-2 lower (C1-6) alkyl groups, lower (C1-6) alkanoyl groups, benzoyl groups, etc. (e.g., amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N,Nxe2x80x2-dimethylamidino, N,Nxe2x80x2-diethylamidino, N-methyl-Nxe2x80x2-diethylamidino, N-formylamidino, N-acetylamidino, etc.), etc.
In the above formula, preferred examples of Rxe2x80x3 include a hydrogen, a lower alkyl group (e.g. C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.), etc. Preferred examples of R include a hydrogen, a lower alkyl group (e.g. C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.), an acyl group (e.g. C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc.; benzoyl; C1-8 alkoxycarbonyl, etc. such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.; C7-10 aralkyloxycarbonyl, etc. such as benzyloxycarbonyl, phenethyloxycarbonyl, etc.), a hydroxy group, etc. Preferred examples of Rxe2x80x2 include a hydrogen, a lower alkyl group (e.g. C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.), an optionally substituted amino group (e.g., an amino group optionally substituted with 1-2 same or different substituents selected from a lower alkyl group (e.g. C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or an acyl group (e.g. C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc.; benzoyl, etc.), a hydrazino group, a 5-6 membered cyclic amino group (e.g., piperidino, thiomorpholino, morpholino, piperazino, etc.), etc.), a hydroxy group, a lower alkoxy group (e.g. C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.), etc.
In the above formula, Rxe2x80x3 and R are preferably hydrogen.
In the above formula, Rxe2x80x2 is preferably hydrogen, a lower alkyl group or an optionally substituted amino group. Among others, Rxe2x80x2 is preferably a lower alkyl group or an optionally substituted amino group, and in particular, an optionally substituted amino group (preferably, amino optionally substituted with C1-4 alkyl, etc.).
Examples of the xe2x80x9cnitrogen-containing heterocyclic groupxe2x80x9d in the xe2x80x9coptionally substituted nitrogen-containing heterocyclic groupxe2x80x9d represented by Z include an aromatic nitrogen-containing heterocyclic group and a saturated or unsaturated non-aromatic nitrogen-containing heterocyclic group (aliphatic heterocyclic group), each of which contains, besides carbon atoms, at least one nitrogen atom (preferably 1 to 3 nitrogen atoms) as an atom constituting a ring system (ring atom) and may contain 1 to 3 hetero-atoms selected from oxygen atom, sulfur atom, etc.
Example of the xe2x80x9caromatic nitrogen-containing heterocyclic groupxe2x80x9d include an aromatic mono cyclic nitrogen-containing heterocyclic group such as pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazol-1-yl, 1H-imidazole-4-yl, etc.), pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thidiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazolyl-1-yl, 1,2,4-triazolyl-4-yl, etc.), tetrazolyl, pyridyl (2-, 3-or 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and N-oxide derivative thereof, etc. Among others, a 5-6 membered aromatic mono cyclic nitrogen-containing heterocyclic group is preferable. In particular, imidazolyl, pyridyl, etc. are preferable.
Example of the xe2x80x9cnon-aromatic nitrogen-containing heterocyclic groupxe2x80x9d include a group formed by partially reducing the above-mentioned xe2x80x9caromatic nitrogen-containing heterocyclic groupxe2x80x9d (e.g., imidazolinyl, tetrahydropyrimidinyl, etc.), and alsoazetidinyl, pyrrolidinyl, piperidyl (2-, 3-or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinyl (1-piperazinyl, etc.), homopiperazinyl, etc. Among others, a 5-6 membered non-aromatic monocyclic nitrogen-containing heterocyclic group is preferable.
As the substituents for the xe2x80x9cnitrogen-containing heterocyclic groupxe2x80x9d represented by Z, the same substituents for the xe2x80x9cheterocyclic groupxe2x80x9d represented by the above-mentioned R1 can be employed. Also, a nitrogen atom constituting the nitrogen-containing heterocyclic group may be oxidized.
As Z, an amidino group or an optionally substituted nitrogen-containing heterocyclic group, etc. are preferable, and in particular, an optionally substituted aromatic nitrogen-containing heterocyclic group, etc. are preferable.
As Compound (I), 1-(4-amidinobenzyl)-4-(6-chloronaphthanlene-2-sulfonyl)-2-piperazinone, 1-(4-5 amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone, 4-(6-chloronaphthanlene-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 1-[1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, 4-(6-chloronaphthanlene-2-sulfonyl)-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, or a salt there of, etc. are preferable.
The pro-drug of the Compound (I) means a compound which is converted to Compound (I) under the physiological conditions or with a reaction due to an enzyme, an gastric acid, etc. in the living body, that is, a compound which is converted to Compound (I) with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to Compound (I) with gastric acid, etc.; etc.
Examples of the pro-drug of Compound (I) include a compound wherein an amino group of Compound (I) is substituted with acyl, alkyl, phosphoric acid, etc. (e.g. a compound wherein an amino group of Compound (I) is substituted with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc.); a compound wherein an hydroxy group of Compound (I) is substituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g. a compound wherein an hydroxy group of Compound (I) is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl group of Compound (I) is modified with ester, amide, etc. (e.g. a compound wherein a carboxyl group of Compound (I) is modified with ethylester, phenylester, carboxymethylester, dimethylaminomethylester, pivaloyloxymethylester, ethoxycarbonyloxyethylester, phthalidylester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylester, cyclohexyloxycarbonylethylester, methylamide, etc.); etc. These pro-drug can be produced by per se known methods from Compound (I).
The pro-drug of Compound (I) may be a compound which is converted into Compound (I) under the physiological conditions as described in xe2x80x9cPharmaceutical Research and Developmentxe2x80x9d, Vol. 7 (Drug Design), pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).
Examples of the salts of the compound (I) include a pharmaceutically acceptable salt, etc. such as an acid addition salt (e.g. a salt with acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphoric acid, hydrochloric acid, nitric acid, hydrobromic acid, hydriodic atom acid, sulfamic acid, sulfuric acid, etc.), a metal salt (e.g. a salt with sodium, potassium, magnesium, calcium, etc.), an organic base (e.g. trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, etc.), etc.
The compounds (I) of this invention can be produced by, for example, methods as described below.
Each compound described in the following reaction schemes may be in the form of a salt, unless it inhibits the reaction and examples of the salts are the same as those of the compound (I).
A compound (II) or a salt thereof represented by the formula:
R1SO2Qxe2x80x83xe2x80x83(II)
wherein Q is a halogen atom, and the other symbol is as defined above is reacted with a compound (II) or a salt thereof represented by the formula:

wherein each symbol is as defined above to produce the compound (I).
In the formula (II), Q is a halogen atom. Examples of the halogen atom represented by Q include fluorine, chlorine, bromine, iodine, etc.
This production method is carried out by reacting a compound (II) or a salt thereof with a compound (III) or a salt thereof. Examples of the salt of the compound (II) or (III) include an acid addition salt with an acid which can form an acid addition salt with the above described compound (I).
This production method is usually carried out in a solvent. Any solvent can be used unless it inhibits this production method.
Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc., ethers such as dioxane, tetrahydrofuran, diethylether, tert-butylmethylether, diisopropylether, ethyleneglycol-dimethylether, etc., esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane etc., hydrocarbons such as n-hexane, benzene, toluene, etc., amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, etc., ketones such as acetone, methylethylketone, methylisobutylketone, etc., nitriles such as acetonitrile, propionitrile, etc., etc., and additionally dimethylsulfoxide, sulfolane (tetramethylene-sulfone), hexamethylphosphorylamide, water, etc., and these can be used singly or as a mixture.
If necessary, this production method can be carried out in the presence of a base. Examples of the base include an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., a tertiary amine such as triethylamine, tri(n-propyl)amine, tri(n-butyl)-amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, xcex3-collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
In the reaction, about 1 to about 5 moles (preferably about 1 to about 3 moles) of the compound (II) is used per 1 mole of compound (III).
The reaction temperature ranges from about xe2x88x9280xc2x0 C. to about 100xc2x0 C., preferably about xe2x88x9250xc2x0 C. to about 80xc2x0 C.
The reaction time varies depending on the kind of compound (II) or (III), kind of solvent, the reaction temperature, etc. and usually ranges from about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.
A compound (IV) or a salt thereof represented by the formula: 
wherein each symbol is as defined above is reacted with a compound (V) or a salt thereof represented by the formula:
Q1xe2x80x94Xxe2x80x2xe2x80x94Xxe2x80x94Yxe2x80x94Xxe2x80x94Zxe2x80x83xe2x80x83(V)
wherein Q1 is a halogen atom or a group of the formula:
R2xe2x80x94SO2xe2x80x94Oxe2x80x94
(wherein R2 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group), and the other symbols are as defined above to produce a compound (I) or a salt thereof.
This production method is carried out by reacting Compound (IV) with Compound (V).
In the above formula (V), examples of the halogen atom represented by Q1 includes chlorine, bromine, iodine, etc.
In the above formula, examples of the lower alkyl group optionally substituted with a halogen atom represented by R2 include C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. Among others, C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc. is preferable.
Examples of the lower alkyl group substituted with a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), which is represented by R2 include trichloromethyl, trifluoromethyl, etc.
Examples of the substituents for the phenyl group represented by R2 include a lower alkyl group (same as the lower alkyl group represented by the above-mentioned R2), a lower alkoxy group (e.g. C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, carboxyl group, etc.
This production method is carried out by reacting Compound (IV) with Compound (V).
This production method is usually carried out in a solvent. Any solvent can be used unless it inhibits this production method.
Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc., ethers such as dioxane, tetrahydrofuran, diethylether, tert-butylmethylether, diisopropylether, ethyleneglycoldimethylether, etc., esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane etc., hydrocarbons such as n-hexane, benzene, toluene, etc., amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, etc., ketones such as acetone, methylethylketone, methylisobutylketone, etc., nitriles such as acetonitrile, propionitrile, etc., etc., and additionally dimethylsulfoxide, sulfolane (tetramethylene-sulfone), hexamethylphosphorylamide, water, etc., and these can be used singly or as a mixture.
If necessary, this production method can be carried out in the presence of a base. Examples of the base include an inorganic base such as alkali metal hydrides (e.g. potassium hydride, sodium hydride, etc.), metal alkoxides having 1 to 6 carbon atoms (e.g. lithium-ethoxide, lithium-tert-butoxide, sodium methoxide, sodium ethoxide, carboxyl-tert-butoxide, etc.), lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., a tertiary amine such as triethylamine, tri(n-propyl)amine, tri(n-butyl)-amine, diisopropylethylamine, dyclohexyldimethylamine, pyridine, lutidine, xcex3-collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
In the reaction, about 1 to about 100 moles (preferably about 1 to about 50 moles) of the compound (V) is used per 1 mole of compound (IV).
The reaction temperature ranges from about xe2x88x9230xc2x0 C. to about 250xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 200xc2x0 C.
The reaction time varies depending on the kind of compound (IV) or (V), kind of solvent, the reaction temperature, etc. and usually ranges from about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.
A compound (VI) or a salt thereof represented by the formula: 
wherein X2 is an optionally substituted alkylene chain, and the other symbols are as defined above and a compound (VII) or a salt thereof represented by the formula:
R3xe2x80x94(Cxe2x95x90O)xe2x80x94X3xe2x80x94Yxe2x80x94Xxe2x80x94Zxe2x80x83xe2x80x83(VII)
wherein X3 is an optionally substituted alkylene chain, R3 is a hydrogen atom or an optionally substituted hydrocarbon group, and the other symbols are as defined above are subjected to reductive amination to give a compound (VIII) or a salt thereof represented by the formula: 
wherein each symbol is as defined above.
In the above formula (VIII), definition of the optionally substituted hydrocarbon group represented by R3 is the same as that shown by R1.
Definition of the substituent for the optionally substituted alkylene chain represented by X2 and X3 is the same as that shown by R1.
Preferred examples of the reducing agent employed in this reductive alkylation include metal hydride complex such as lithium aluminum hydride, trimethoxy lithium aluminum hydride, tri-tert-butoxy lithium aluminum hydride, aluminum sodium hydride, triethoxy aluminum sodium hydride, sodium boron hydride, trimethoxy sodium boron hydride, sodium boron cyanide hydride, triacetoxy sodium boron hydride, lithium boron hydride, lithium boron cyanide hydride, triethyl lithium boron hydride, etc. In addition, catalytic reduction (catalytic hydrogenation) can be employed. Examples of the catalyst include palladium catalysts such as palladium black, palladium carbon, palladium-silica gel, palladium-barium sulfate, etc., platinum catalysts such as oxidized platinum, platinum carbon, platinum black, etc., rhodium catalysts such as rhodium carbon, rhodium almina, etc., ruthenium catalysts such as oxidized ruthenium, ruthenium carbon, etc., Raney nickel, etc. Said catalytic reduction is carried out under a hydrogen atmosphere. Amount of the catalyst to be employed ranges from about 0.0001 to about 2 mole, preferably about 0.001 to about 1 mole per mole of Compound (VI). The reduction reaction is usually carried out under atmospheric pressure but, if necessary, can be carried out under high pressure. Said pressure ranges from about 1 to about 150 times atmospheric pressure, preferably about 1 to about 100 times atmospheric pressure.
The reaction is usually carried out in a solvent. Any solvent can be used unless it inhibits this production method.
Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc., ethers such as dioxane, tetrahydrofuran, diethylether, tert-butylmethylether, diisopropylether, ethyleneglycol-dimethylether, etc., esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane etc., hydrocarbons such as n-hexane, benzene, toluene, etc., amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, etc., and additionally dimethylsulfoxide, sulfolane (tetramethylenesulfone), hexamethylphosphorylamide, water, etc., and these can be used singly or as a mixture.
If necessary, this production method can be carried out in the presence of an acid. Examples of the acid include a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchlorate, etc., a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphor sulfonic acid, etc., an organic acid such as formic acid, acetic acid, propionic acid, etc.
In the reaction, about 0.01 to about 20 moles (preferably about 0.1 to about 10 moles) of the acid is used per 1 mole of Compound (VI), and about 1 to about 2 moles of Compound (VII) is used per 1 mole of Compound (VI).
The reaction temperature ranges from about xe2x88x9230xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 120xc2x0 C.
The reaction time varies depending on the kind of compound (VI) or (VII), kind of solvent, the reaction temperature, etc. and usually ranges from about 10 minute to about 72 hours, preferably about 15 minutes to about 48 hours.
Compound (VIII) is further reacted with Compound (IX) represented by the formula:
Q2xe2x80x94X4xe2x80x94COOHxe2x80x83xe2x80x83(IX)
wherein X4 is an optionally substituted alkylene chain, Q2 is a halogen atom or a group of the formula:
R4xe2x80x94SO2xe2x80x94Oxe2x80x94
(wherein R4 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group), and the other symbols are as defined above to produce Compound (X) represented by the formula: 
wherein each symbol is as defined above.
In the above formula, Q2 is a halogen atom or a group of the formula:
R4xe2x80x94SO2xe2x80x94.
In the above formula, example of the halogen atom represented by Q2 includes chlorine, bromine, iodine, etc. R4 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group. Example of the lower alkyl group represented by R4 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. Among others, methyl, ethyl, propyl, isopropyl, butyl, etc. are preferable. Examples of the halogen atom include fluorine, chlorine, bromine, iodine, etc. At any possible position, 1 to 9 (preferably 1 to 5) of these halogen atoms may be substituted.
Examples of the substituents for the optionally substituted phenyl group include lower alkyl (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, butyl, etc.), lower alkoxy group (e.g., C1-6 alkoxy group such as methoxy, ethoxy, propoxy, butoxy, etc.), ahalogenatom (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, carboxyl group, etc.
This production method is carried out by reacting a compound (VIII) or a salt thereof with a free acid (IX) or a salt thereof (inorganic salt, organic salt, etc.) or its reactive derivatives (e.g. acid halide, acid azide, acid anhydride, mixed acid anhydride, active amide, active ester, active thioester, etc.). Examples of the salt of the compound (VIII) include an acid addition salt with an acid which can form an acid addition salt with the above described compound (I).
Examples of the inorganic salt of the compound (IX) include a salt with alkali metal (e.g. a salt with sodium, potassium, etc.), a salt with alkaline earth metal (e.g. a salt with calcium, etc.), etc. Examples of the organic salt of the compound (IX) include a salt with trimethylamine, triethylamine, tert-butyldimethylamine, dibenzylmethylamine, benzyl-dimethylamine, N,N-dimethylaniline, pyridine, quinoline, etc.
Examples of the acid halide include acid chloride, acid bromide, etc. Examples of the mixed acid anhydride include mono-C1-4 alkyl carbonate mixed acid anhydride (e.g. a mixed acid anhydride of a free acid (IX) with monomethylcarbonate, monoethylcarbonate, monoisopropyl-carbonate, monoisobutylcarbonate, mono-(tert-butyl)carbonate, mono-benzylcarbonate, mono(p-nitrobenzyl)carbonate, monoallylcarbonate, etc.), C1-6 alicyclic carboxylic acid mixed acid anhydride (e.g. a mixed acid anhydride of a free acid (IX) with acetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, etc.), C7-11 aromatic carboxylic acid mixed acid anhydride (e.g. a mixed acid anhydride of a free acid (IX) with benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc.), organic sulfonic acid mixed acid anhydride (e.g. a mixed acid anhydride with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), etc. Examples of the active amide include an amide with nitrogen-containing heterocyclic compound (e.g. an acid amide of a free acid (IX) with pyrazole, imidazole, benzotriazole, etc.; Said nitrogen-containing heterocyclic compound is optionally substituted with C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), a halogen atom (e.g. fluorine, chlorine, bromine, etc.), oxo, thioxo, C1-6 alkylthio (e.g. methylthio, ethylthio, propylthio, butylthio, etc.), etc.), etc.
Examples of the active ester include organic phosphoric acid ester (e.g. diethoxyphosphoric acid ester, diphenoxyphosphoric acid ester, etc.), p-nitrophenylester, 2,4-dinitrophenylester, cyanomethylester, pentachlorophenylester, N-hydroxysuccinimide ester, N-hydroxy-phthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1-hydroxy-benzotriazole ester, 1-hydroxy-1H-2-pyridone ester, etc.
Examples of the active thioester include ester with aromatic heterocyclic thiol compound (e.g. 2-pyridylthiol ester, 2-benzo-thiazolylthiol ester), etc., said heterocyclic group being optionally substituted with C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), a halogen atom (e.g. fluorine, chlorine, bromine, etc.), C1-6 alkylthio (e.g. methylthio, ethylthio, propylthio, butylthio, etc.), etc.
This production method is usually carried out in a solvent and, if necessary, in the presence of a base or a condensing agent (e.g. carbodiimides (e.g. DCC, WSC, DIC, etc.), phosphoric acid derivatives (e.g. cyanophosphorate diethyl, DPPA, BOP-Cl, etc.), etc.).
Examples of the solvent are the same as those described in the above Method A.
In the reaction, about 1 to about 5 moles (preferably about 1 to about 2 moles) of Compound (IX) is used per 1 mole of Compound (VIII).
The reaction temperature ranges about xe2x88x9250xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9220xc2x0 C. to about 10xc2x0 C.
The reaction time varies depending on the kind of compound (VIII) or (IX), kind of solvent and base, the reaction temperature, etc. and usually ranges from about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours.
Compound (X) is subjected to ring-closure reaction to produce Compound (Ia) or a salt thereof represented by the formula: 
wherein each symbol is as defined above.
This ring-closure reaction is usually carried out in the presence of a base. Preferred examples of the base include an inorganic base such as alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkali metal hydroxide (e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), etc.,; an organic acid such as trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, etc.; a lithium salt such as methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc., a lithium amide such as lithium diisopropylamide, etc.
This reaction is usually carried out in a solvent. Examples of the solvent are the same as those described in the above Method A.
In the reaction, about 1 to about 100 moles (preferably about 1 to about 20 moles) of the base is used per 1 mole of the compound (I). If necessary, the base can be used as a solvent.
The reaction temperature ranges about xe2x88x92100xc2x0 C. to about 200xc2x0 C., preferably about xe2x88x9278xc2x0 C. to about 150xc2x0 C.
The reaction time varies depending on the kind of compound (X), kind of solvent and base, the reaction temperature, etc. and usually ranges from about 1 minute to about 200 hours, preferably about 5 minutes to about 100 hours.
A compound (XI) or a salt thereof represented by the formula: 
wherein X5 is an optionally substituted alkylene chain, and the other symbols are as defined in the above (1) is reacted with a compound (XII) or a salt thereof represented by the formula:
Zxe2x80x94Xxe2x80x94Yxe2x80x94X6xe2x80x94NHCH2CH(OR5)2xe2x80x83xe2x80x83(XII)
wherein X6 is an optionally substituted alkylene chain, R5 is lower alkyl group, and the other symbols are as defined above to produce Compound (XIII) represented by the formula: 
wherein each symbol is as defined above.
In the above formula, as the substituents in the optionally substituted alkylene chain represented by X5 and X6, those exemplified in the optionally substituted hydrocarbon group represented by R1 can be employed.
Examples of the lower alkyl group represented by R5 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. Among others, methyl, ethyl, propyl, isopropyl, butyl, etc. are preferable.
In this reaction, reactive derivatives, reaction condition, reaction solvent, reaction time, etc. to be employed are the same as reactive derivatives, reaction condition, etc. exemplified in the reaction between Compound (VIII) and Compound (IX) in the method C or an analogous method thereto.
Compound (XIII) is subjected to ring-closure reaction to convert Compound (XIV) represented by the formula; 
wherein each symbol is as defined above.
This ring-closure reaction is usually carried out in the presence of an acid. Examples of such an acid catalyst include carboxylic acid such as formic acid, acetic acid, propionic acid, benzoic acid, etc., sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, camphor-sulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc., inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. Also, polyphosphoric acid, polyphosphoric acid ester, etc. can be used as the acid, and in some cases, Lewis acid can be used. Examples of the Lewis include tin chloride, zinc chloride, aluminum chloride, titaniumchloride, tinbromide, zincbromide, aluminum bromide, titanium bromide, and additionally, boron fluoride, etc.
This reaction is usually carried out in a solvent. As the solvent, any solvent can be selected as far as it does not inhibit the reaction. Examples of the solvent are the same as those described in the above Method A.
In the reaction, about 0.001 to about 100 moles of the acid is used per 1 mole of the compound (XIV). If necessary, the acid can be used as a solvent.
The reaction temperature ranges about xe2x88x9250xc2x0 C. to about 200xc2x0 C., preferably about xe2x88x9230xc2x0 C. to about 150xc2x0 C.
The reaction time varies depending on the kind of compound (XIV) or acid, kind of solvent, the reaction temperature, etc. and usually ranges from about 10 minutes to about 48 hours, preferably about 20 minutes to about 24 hours.
If desired, Compound (XVI) is subjected to reduction of a double bond to produce Compound (Ib) or a salt thereof represented by the formula: 
wherein a combination of a broken line and a full line is a single bond or a double bond, and the other symbols are as defined above.
Examples of the reduction agent to be employed for this reduction reaction include metal and acid. Examples of the metal include zinc, tin, iron, etc., Examples of the acid include carboxylic acidsuchas formic acid, acetic acid, propionicacid, etc., inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., etc. Also, the reduction method mentioned in method C or an analogous method thereto can be employed, and any other reduction method may be employed as far as it does not inhibit the reaction.
This reaction is usually carried out in a solvent. As the solvent, any solvent can be selected as long as it does not inhibit the reaction. Examples of the solvent are the same as those described in the above Method C.
In the reaction, about 0.1 to about 100 moles of the reduction agent is used per 1 mole of the compound (XIV).
The reaction temperature ranges about xe2x88x9230xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 120xc2x0 C.
The reaction time varies depending on the kind of compound (XIV), kind of reduction agent, kind of solvent, the reaction temperature, etc. and usually ranges from about 10 minutes to about 72 hours, preferably about 15 minutes to about 48 hours.
Compound (XX) or a salt thereof represented by the formula: 
wherein each symbol is as defined above is reacted with Compound (XXI) or a salt thereof represented by the formula:
Zxe2x80x94X7xe2x80x94Q3
wherein X7 is a chemical bond or an optionally substituted alkylene chain, Q3 is a halogen atom or a group of the formula:
R6xe2x80x94SO2xe2x80x94Oxe2x80x94
(wherein R6 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group), and the other symbol is as defined above to produce Compound (I).
In the above formula, as the substituents for the optionally substituted alkylene chain represented by X7, those exemplified in the optionally substituted hydrocarbon group represented by R1 can be employed.
In the above formula, examples of the halogen atom represented by Q3 include chlorine, bromine, iodine, etc.
In the above formula, R6 is a lower alkyl group optionally substituted with a halogen atom or an optionally substituted phenyl group. Examples of the lower alkyl group represented by R6 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and among others, methyl, ethyl, propyl, isopropyl, butyl, etc. are preferable. Examples of the halogen atom include fluorine, chlorine, bromine, iodine, etc. Said lower alkyl group may have at optional position 1 to 9, preferably 1 to 5 halogen atoms. Examples of the substituents in the optionally substituted phenyl group include lower alkyl (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, butyl, etc.), lower alkoxy group (e.g., C1-6 alkoxy group such as methoxy, ethoxy, propoxy, butoxy, etc.), ahalogenatom (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, carboxyl group, etc.
This method is to produce Compound (I) by reacting compound (XX) or a salt thereof with Compound (XXI) or a salt thereof.
This reaction is usually carried out in the presence of abase. Preferred examples of the base include an inorganic base such as alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkali metal hydroxide (e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), etc.,; an organic acid such as trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, etc.; a lithium salt such as methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc., a lithium amide such as lithium diisopropylamide, etc.
This reaction is usually carried out in a solvent. Examples of the solvent are the same as those described in the above Method A.
In the reaction, about 0.8 to 10 moles (preferably about 0.9 to 5 moles) of Compound (XXI) and about 1 to about 100 moles (preferably about 1 to about 20 moles) of the base are used per 1 mole of the compound (XX). If necessary, the base can be used as a solvent.
The reaction temperature ranges from about xe2x88x9210xc2x0 C. to about 250xc2x0 C., preferably about xe2x88x925xc2x0 C. to about 200xc2x0 C.
The reaction time varies depending on kind of Compound (XX), Compound (XXI), base or solvent, the reaction temperature, etc. and usually ranges from about 1 minute to about 200 hours, preferably about 5 minutes to about 100 hours.
This reaction can be promoted, in some cases, by using metal catalyst. Examples of the catalyst include palladium compound [e.g., palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride, dichlorobis(triethylphosphine)palladium, tris(dibenzylideneacetone)dipalladium-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, etc.], nickel compound [e.g., tetrakis(triphenylphosphine)nickel, bis(triethylphosphine)nickel chloride, bis(triphenylphosphine)nickel chloride, etc.], rhodium compound [e.g., tri(triphenylphosphine)rhodium chloride, etc.], etc. Among others, palladium compound is preferable. The amount of the catalyst is about 1 to 0.000001 mole, preferably about 0.1 to 0.00001 mole per 1 mole of the compound (XX).
Also, this reaction may be carried out in a sealed tube.
(Production of Compound (I) wherein Z is an optionally substituted amidino group)
Compound (XXII) or a salt thereof represented by the formula: 
wherein each symbol is as defined above is reacted with Compound (XXIII) or a salt thereof represented by the formula:
R7OH
wherein R7 is lower alkyl group to produce Compound (XXIV) or a salt thereof represented by the formula: 
wherein each symbol is as defined above, followed by reacting Compound (XXIV) or a salt thereof with amine to produce Compound (XXV) or a salt thereof represented by the formula: 
wherein Zxe2x80x2 is an optionally substituted amidino group, and the other symbols are as defined above.
In the above formula, examples of the lower alkyl group represented by R7 include C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc., etc.
The reaction between Compound (XXII) and Compound (XXIII) is usually carried out in a solvent. Examples of the solvent are the same as those described in the above Method A. Compound (XXIII) itself may be used as the solvent.
This reaction is usually carried out in the presence of an acid (e.g., inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., organic acid such as methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, acetic acid, trifluoroacetic acid, etc., etc.) and an base (e.g., potassium methoxide, sodium methoxide, sodium ethoxide, potassium-tert-butoxide, etc.). The amount of the acid and the base varies catalytic amount (about 0.001 mole) to excess amount.
The reaction temperature ranges from about xe2x88x9250xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9220xc2x0 C. to about 100xc2x0 C.
The reaction time varies depending on kind of Compound (XXII), acid, base or solvent, etc. and usually ranges from bout 30 minutes to about 240 hours, preferably about 1 hour to about 120 hours.
Compound (XXIV) is reacted with amine (e.g., primary amine such as ammonia; methylamine, ethylamine, propylamine, etc.; secondary amine such as dimethylamine, diethylamine, methylethylamine, di-n-propylamine, pyrrolidine, piperidine, morpholine, piperazine, 1-methylpiperazine, etc.; aromatic amine such as aniline, N-methylaniline, etc.; etc.) to produce Compound (XXV).
This reaction is usually carried out in a solvent. As the solvent, any solvent can be employed as long as it does not inhibit the reaction. The solvent exemplified in the above Method A is preferably employed, and also amine itself may be employed as the solvent.
The reaction temperature ranges about xe2x88x9220xc2x0 C. to about 200xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 150xc2x0 C.
The reaction time varies depending on kind of Compound (XXIV), amine and solvent, and reaction temperature and usually ranges from about 30 minutes to about 240 hours, preferably about 1 hour to about 120 hours.
If necessary, this reaction may be carried out in a sealed tube.
Compounds (II), (III), (IV), (V), (VI), (VII), (IX), (XI), (XII), (XX) and (XXII) employed as starting materials in the above-mentioned production methods A to F can be produced per se known methods or a similar method thereto.
a) Production Method of Compound (II)
i) 
xe2x80x83wherein each symbol is as defined above
This production method is carried out by halogenation of the compound (XV) or a salt thereof (inorganic salt, organic salt, etc.). Examples of the inorganic salt of the compound (XV) include a salt with alkali metal (e.g. a salt with sodium, a salt with potassium, etc.), a salt with alkaline earth metal (e.g. a salt with calcium, etc.). Examples of the organic salt of the compound (XV) include a salt with trialkylamine (e.g. a salt with trimethylamine, triethylamine, tert-butyldimethylamine, diisopropylethylamine, etc.), a salt with an aromatic tertiary amine (e.g. N,N-dimethylaniline, pyridine, quinoline, etc.). Examples of a halogenating agent include e.g. phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorylchloride, phosphorylbromide, thionylchloride, thionyl-bromide, etc.
The reaction can be carried out by reacting the compound (XV) with the halogenating agent as a solvent in the presence of no other solvent. The reaction can be carried out in the presence of a solvent other than the halogenating agent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, diethylether, diisopropyl-ether, dimethoxyethane, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc., aromatic hydrocarbons such as benzene, toluene, chlorobenzene, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., and these can be used singly or as a mixture.
In the reaction, about 1 to about 100 moles (preferably about 1 to about 50 moles) of the halogenating agent is used per 1 mole of the compound (XV). The reaction temperature ranges from about xe2x88x9230xc2x0 C. to about 250xc2x0 C., preferably about xe2x88x9220xc2x0 C. to about 200xc2x0 C. The reaction time varies depending on kind of the compound (XV) or the halogenating agent, kind of the solvent, the reaction temperature, etc. and usually ranges from about 1 minute to about 72 hours, preferably about 10 minutes to about 24 hours.
ii) 
xe2x80x83wherein L1 is a hydrogen atom or a leaving group, and the other symbols are as defined above.
This production method is carried out by reacting the compound (XVI) with chlorine or bromine in the presence of water to produce the compound (II). Examples of the leaving group represented by L1 include xe2x80x94CN, xe2x80x94SO3Na, xe2x80x94C(xe2x95x90NH)NH2, etc.
The reaction is usually carried out in a solvent and preferable examples of the solvent include that exemplified in the above described Method C. In the reaction, about 1 to about 100 moles, preferably about 1 to about 30 moles of the chlorine or bromine is used per 1 mole of the compound (XVI). The reaction temperature ranges from about xe2x88x9250xc2x0 C. to about 180xc2x0 C., preferably about xe2x88x9230xc2x0 C. to about 120xc2x0 C.
There are many known methods for producing a sulfonyl chloride or a sulfonyl bromide of the compound (II) and the compound (II)can be produced by the above method i) or ii) as well as known methods or a method similar thereto.
b) Production Method of the Compound (III) 
wherein L2 is a protective group for an amino group, and other symbols are as defined above.
In the above formulas (XVII) and (XVIII), examples of the protective group represented by L2 include formyl group, C1-6 alkyl-carbonyl group (e.g. acetyl, ethylcarbonyl, etc.), benzyl group, tert-butyloxycarbonyl group, benzyloxy-carbonyl group, allyloxycarbonyl group, phenylcarbonyl group, C1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), C7-10 aralkyl-carbonyl group (e.g. benzylcarbonyl, etc.), trityl group, etc. These protective groups may be substituted with 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, etc.), nitro group, etc.
This production method is carried out by reacting the compound (XVII) with a compound (V) or its reactive derivatives to produce the compound (XVIII).
The reaction conditions of this production method is the same as described in the above Method B. The compound (III) can be produced by removing the protective group of the compound (XVIII).
Examples of the method for removing the protective group include per se known methods or a similar method thereto such as a method using acid, base, reduction, ultraviolet light, palladium acetate, etc.
C) Production Method of the Compound (IV) 
wherein each symbol is as defined above This production method is carried out by reacting the compound (II) with the compound (XIX) to produce the compound (IV). The reaction conditions of this production method is the same as described in the above Method A.
Compounds (V), (VI), (VII), (IX), (XI) and (XII) can be produced by per se known methods or a similar method thereto.
When a free form of the compound is obtained according to the above described reaction of the present invention, it can be transformed into a salt thereof according to per se methods. When a salt of the compound is obtained according to the above described reaction of the present invention, it can be transformed into a free form or the other salt thereof according to per se methods.
The compound (I) of this invention can be isolated from the reaction mixture by conventional method separation and purification means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and thin-layer chromatography, etc.
Salts of the compound (I) can be obtained by per se known methods, e.g. by adding an inorganic acid or an organic acid to the compound (I).
When stereoisomers are present in the compounds (I), individual isomers or a mixture thereof are included in the scope of the present invention. And, it is also possible to produce these isomers individually. The compounds (I) may be hydrated.
The compounds (I) of the present invention or a salt thereof are low in toxicity, inhibit FXa and have anti-coagulant activity, theref ore, they are useful for the prevention or treatment of the following diseases of animals, especially mammals (e.g. human, monkey, cat, pig, horse, cow, mouse, rat, guineapig, dog, rabbit, etc.). Among others, they are preferably used for the prevention or treatment of cerebral infarction (especially due to atrial fibrillation or auricular fibrillation), deep vein thrombosis, etc.
Brain:
cerebral infarction due to atrial fibrillation or auricular fibrillation, acute ischemic cerebral apoplexy, acute phase cerebral thrombosis, cerebral vasospasm after subarachnoid hemorrhage, Alzheimer""s disease, transient ischemic attack (TIA), mixed dementia, cerebrovascular dementia, multiple sclerosis dementia,
Heart:
acute cardiac infarction, sequela of cardiac infarction, unstable angina, angina pectoris, reobturation or restenosis after coronary intervention such as stent-indwelling or PTCA (percutaneous transluminol coronary angioplasty) and atherectomy,
Periphery:
deep vein thrombosis, peripheral arterial obstruction, adult respiratory distress syndrome (ARDS), chronic renal disease (e.g. diabetic nephropathy, chronic glomerulonephritis, IgA nephropathy, etc.), diabetic cardiovascular disorder, diabetic pain, diabetic nerve disturbance,
Others:
thrombocytopenia due to dialysis, thrombocytopenia due to operation, arteriosclerosis, cancer metastasis, systemic inflammation reaction syndrome (SIRS) or disseminated intravascular coagulation (DIC) in cases of pancreatitis, sepsis or cancer, rejection after transplantation, protecting organs or ameliorating finction of organs after transplantation, various organ failures (e.g. pulmonary failure, hepatic insufficiency, renal insufficiency, heart failure, etc.) due to shock or DIC.
The compound (I) of the present invention or a salt thereof, alone or in combination with a pharmaceutically acceptable carrier, can be administered orally or non-orally.
Examples of pharmaceutical composition for oral administration of the compound (I) or a salt thereof of the present invention include tablets (including sugar-coated tablet, film coating tablet), pills, granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions, etc. Examples of pharmaceutical composition for non-oral administration of the compound (I) or a salt thereof of the present invention include injections, inhalants, drops, suppositories, etc.
The content of the compound (I) or a salt thereof in the pharmaceutical composition of this invention varies depending on the kind of formulations and is usually about 2 to about 85 weight %, preferably about 5 to about 70 weight % based on the total weight of the composition.
Examples of the method for preparing the pharmaceutical compositions containing the compound (I) or a salt thereof include conventional methods generally used in this field. In addition, when the above pharmaceutical compositions are prepared, if desired, an appropriate amount of an additive which is generally used in this field such as an excipient, a binder, an disintegrating agent, a lubricant, a sweetener, a surfactant, a suspending agent, an emulsifier, etc. can be added to the compositions.
For example, a tablet of the compound (I) or a salt thereof may contain an excipient, a binder, an disintegrating agent, a lubricant, etc.; a pill and a granulate may contain an excipient, a binder, an disintegrating agent, etc.; a powder and a capsule may contain an excipient, etc.; a syrup may contain a sweetener, etc.; and an emulsion or a suspension may contain a surfactant, a suspending agent, an emulsifier, etc.
Examples of the excipient include lactose, sucrose, glucose, starch, fine crystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogen carbonate, calcium phosphorate, calcium sulfate, etc.
Examples of the binder include 5 to 10 weight % of starch solution, 10 to 20 weight % of gum arabic or gelatin solution, 1 to 5 weight % of traganth solution, carboxy-methylcellulose solution, sodium alginate solution, glycerin, etc.
Examples of the disintegrating agent include starch, calcium carbonate,etc.
Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc, etc.
Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup, etc.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan mono fatty acid ester, stearic acid polyoxyl 40, etc.
Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methyl-cellulose, bentonite, etc.
Examples of the emulsifier include gum arabic, traganth, gelatin, polysorbate 80, etc.
In addition, when the above described compositions are prepared, if desired, an appropriate amount of a colorant, a preservative, an aromatic, a flavoring, a stabilizer, a viscous liquid, etc. which is generally used in this field can be added to the compositions.
The compound (I) or a salt thereof is low in toxicity and stable, therefore, it can be used safely. While the dosage of the compound (I) can vary with condition or body weight of patients, kind of the compound and administration routes, etc., when administered orally to a patient of e.g. thrombosis, a dose of about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg of the active ingredient [compound (I)], per day for an adult (body weight: about 60 kg), divided into one to three times, is appropriate.
When Compound (I) or a salt thereof of the present invention is non-orally administered, it is usually administered in the form of a liquid preparation (e.g. injection). Unit dosage varies depending on subject or organ to be administered to symptom, administration route, etc. For example, when administered in the form of injection, preferred unit dosage of intravenous injection usually ranges from about 0.01 mg to about 100 mg, preferably about 0.01 to about 50 mg, and more preferably about 0.01 to about 20 mg per 1 kg body weight. Examples of the injection include subcutaneous injection, intracutaneous injection, intramuscular injection, drip, etc. Examples of the sustained release preparation include iontophoresis transdermal agent, etc.
Said injection is prepared by a per se known method, that is, by dissolving, suspending or emulsifying Compound (I) or a salt thereof of the present invention in sterilized aqueous or oily solution.
Examples of the aqueous solution for injection include isotonic solution comprising isotonic sodium chloride solution brine, glucose or the other additive (e.g., D-sorbitol, D-mannitol, sodium chloride, etc.), etc., and an appropriate solubilizing agent such as alcohol(e.g. ethanol), polyalcohol (e.g. propyleneglycol, polyethyleneglycol), non-ionic surfactant (e.g. polysorbate 80, HCO-50), etc. may be combined. Examples of the oily solution for injection include sesame oil, soybean oil, etc., and an solubilizing agent such as benzyl benzoate, benzylalcohol, etc. may be combined. In addition, buffer solution (e.g., phosphoric acid buffer solution, sodium acetate buffer solution), soothing agent (e.g., benzalkonium chloride, procaine hydrochlide, etc.), stabilizing agent (e.g., human serum albumin, polyethyleneglycol, etc.), preservative (e.g., benzylalcohol, phenol, etc.), etc. maybe combined. Thus prepared injection is usually filled in ampoules.
The pharmaceutical composition of the present invention can be used in combination with thrombolytic drug (e.g. tPA, heparin, urokinase, etc.), drug for treating Alzheimer""s disease (e.g. Avan, Calan, etc.), drug for treating cholesterol (e.g. HMG-CoA reductase inhibitor such as Simvastatin, Pravastatin, etc., etc.), TG (triglyceride) decreasing drug (antihyperlipoproteinemic agent) (e.g. Clofibrate, etc.), AII antagonist (e.g. Blopress, etc.), anti-thrombocyte drug (e.g. aspirin, etc.), Ca antagonist (e.g. Calslot, Amlodipine, etc.) etc., or the active ingredient of these drugs can be added to the pharmaceutical composition of the present invention.
The present invention is hereinafter described in more detail by means of the following Reference Examples, Working Examples, Formulation Examples and Experimental Examples which are not to be construed as limitative. Also, the following embodiments may be modified within, the scope of the present invention.
Elution in column chromatography in Reference Examples and Working Examples was observed under TLC (Thin Layer Chromatography). In the TLC observation, silica gel 60F254 (Merck) was used as a TLC plate, a solvent used for eluting the column chromatography was used as a mobile phase, and UV detector was employed for detection. Kiesel gel 60 (70 to 230 mesh; Merck) was used for a silica gel column chromatography.